Force-Induced Unfolding Simulations of the Human Notch1 Negative Regulatory Region Possible Roles of the Heterodimerization Domain in Mechanosensing 英文参考文献.docVIP

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Force-Induced Unfolding Simulations of the Human Notch1 Negative Regulatory Region Possible Roles of the Heterodimerization Domain in Mechanosensing 英文参考文献.doc

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Force-Induced Unfolding Simulations of the Human Notch1 Negative Regulatory Region Possible Roles of the Heterodimerization Domain in Mechanosensing 英文参考文献

Force-InducedUnfoldingSimulationsoftheHuman Notch1NegativeRegulatoryRegion:PossibleRolesof theHeterodimerizationDomaininMechanosensing JianhanChen*,AnnaZolkiewska* DepartmentofBiochemistry,KansasStateUniversity,Manhattan,Kansas,UnitedStatesofAmerica Abstract NotchreceptorsarecorecomponentsoftheNotchsignalingpathwayandplayacentralroleincellfatedecisionsduring developmentaswellastissuehomeostasis.Uponligandbinding,NotchissequentiallycleavedattheS2sitebyanADAM proteaseandattheS3sitebythec-secretasecomplex.RecentX-raystructuresofthenegativeregulatoryregion(NRR)of theNotchreceptorrevealanauto-inhibitedfoldwherethreeprotectiveLin12/Notchrepeats(LNR)oftheNRRshieldtheS2 cleavagesitehousedintheheterodimerization(HD)domain.Oneofthemodelsexplaininghowligandbindingdrivesthe NRRconformationfromaprotease-resistantstatetoaprotease-sensitiveoneinvokesamechanicalforceexertedonthe NRRuponligandendocytosis.Here,wecombinedphysics-basedatomisticsimulationsandtopology-basedcoarse-grained modelingtoinvestigatetheintrinsicandforce-inducedfoldingandunfoldingmechanismsofthehumanNotch1NRR.The simulations support that external force applied to the termini of the NRR disengages the LNR modules from the heterodimerization(HD)domaininawell-defined,largelysequentialmanner.Importantly,themechanicalforcecanfurther drivelocalunfoldingoftheHDdomaininafunctionallyrelevantfashionthatwouldprovidefullproteolyticaccesstotheS2 sitepriortoheterodimerdisassociation.Wefurtheranalyzedlocalstructuralfeatures,intrinsicfoldingfreeenergysurfaces, and correlated motions of the HD domain. The results are consistent with a model in which the HD domain possesses inherent mechanosensing characteristics that could be utilized during Notch activation. This potential role of the HD domain in ligand-dependent Notch activation may have implications for understanding normal and aberrant Notch signaling. Citation: Chen J, Zolkiewska A (2011) Force-Induced Unfolding Simulations of the Human Notch1 Negative Regulatory Region: